Date of Award

5-2026

Document Type

Thesis

Degree Name

Master of Science (MS)

College/School

College of Science and Mathematics

Department/Program

Chemistry and Biochemistry

Thesis Sponsor/Dissertation Chair/Project Chair

Nina Goodey

Committee Member

David Rotella

Committee Member

Kathleen Frey

Abstract

Lymphatic filariasis, a neglected tropical disease caused by the parasitic worm Wuchereria bancrofti (Wb). We are investigating the dihydrofolate reductase (DHFR) of Wb as a potential drug target due to DHFR’s ability to catalyze the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF). Methotrexate (MTX) was found to potently inhibit Wb DHFR with IC₅₀ and Kᵢ values of 0.023 μM and 0.0016 μM, respectively. MTX is known to inhibit human DHFR (h. DHFR), posing concerns about cross reactivity and side effects. Wb DHFR was crystallized in complex with MTX, TSD 001, TSD 10, TSD 13 and TSD 25 to understand active site interactions. One of the key interactions observed in these structures was a hydrogen bond and a salt bridge with the side chain carboxylic acid of Arg72. TSD 10, however, did not show these interactions. The methoxy group attached in the para position of the benzoic acid in TSD 10, likely caused Arg72 to shift away, perhaps contributing to the lower affinity to Wb DHFR compared to TSD 001, TSD13 and TSD25. This observation highlights the importance of Arg72 in inhibitor binding. Helical peptide mimetic compounds (Oligo) and Propargyl linked antifolates (PLA) were assessed for their potency through inhibition assay. The IC₅₀ values for the oligo compounds ranged between 19 μM and 0.3 μM. For the PLA compounds, it ranged between 6 μM and 0.006 μM. The goal of this project is to repurpose known DHFR inhibitors and optimize them to treat lymphatic filariasis.

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